Approximately 100 million surgeries are performed each year in the US and systemic opioids are used to manage postoperative pain, and pain is only adequately controlled in half of patients. Opioid postoperative pain management prescriptions are fueling the opioid epidemic as 1.6 million U.S. surgical outpatient become long-term opioid users each year with 10% of these becoming addicted to opioids. This dire scenario is a result of permissive opioid prescribing, and inadequate pain coverage particularly within the first 24 hours post-surgery. Moreover, only 38% of opioids prescribed at discharge are used leaving a huge reservoir of pills available for misuse and illicit diversion.
In an effort to reduce the need for opioid medications, anesthetics are administered locally, via an epidural injection, peripheral nerve block, or local infiltration. Unfortunately, the duration of action of presently approved anesthetics is less than 12 hours. The 24-hour period immediately following surgery is the most painful and requires robust analgesia coverage to ensure pain relief and opioid abstinence. As more outpatient surgeries are being performed, adequate pain control upon discharge is crucial.
A prolonged-release formulation of the approved anesthetic, bupivacaine encapsulated within liposomes (EXPAREL®) provides a longer duration of action compared to aqueous bupivacaine, pain relief is generally only for 24 hours with an associated slight reduction in opioid use.
In a Phase 2 bunionectomy study using HTX-011, a pharmaceutical formulation comprising an anti-inflammatory, meloxicam, and bupivacaine poly (ortho ester) to treat post-operative pain, 16% of patients remained opioid free post bunionectomy, compared to 7% of patients using aqueous bupivacaine alone. Viscusi, 2017, J Am Coll Surg, 225(Supp 2):e37.
Research effort has been made to synthesize hydrolysis-resistant polyester-poly(lactic acid-co-castor oil) for sustained release formulations of bupivacaine. Bupivacaine has been incorporated into hydrophobic, hydrolysis-resistant polyester-poly(lactic acid-co-castor oil) at 10% (w/v), resulting in a slower degradation rate, prolonged drug release, and 1-2 days of nerve block. Sokolsky-Papkov, 2009; Pharma Res, 3:7-10, and Sokolsky-Papkov; 2010, J Pharma Sci, 99: 2732-38. This fatty acid based biodegradable polymer released 60% of stored bupivacaine during one week without a burst of drug release. A single injection of the formulation caused motor blockade for 64 hours and sensory blockade for 96 hours. However, the formulation suffered significant burst release that led to systemic toxicity. Increasing the bupivacaine concentration to 15% (w/v) prolonged the duration of sensory blockade to 96 hours and exhibited less burst release than with 10% bupivacaine. This effect was attributed to increased formulation density and hydrophobicity, resulting in reduced water penetration into the drug-polymer matrix.
10% (w/v) bupivacaine in injectable and biodegradable poly(sebacic-co-ricinoleic acid) was shown to prolong sciatic nerve blockade from 8 to 30 hours. Shikanov, 2007, J Control Release 117:97-103. Incorporation of anhydride bonds (which undergo hydrolysis) in the polymer backbone rendered the formulation biodegradable. In vitro, 70% of the incorporated drug was released over the course of one week.
Much effort has been made to develop controlled release local anesthetic drug products. The drug delivery vehicle typically consists of a polymeric matrix from which drug is released by diffusion and/or degradation of the matrix. The local anesthetic is typically entrapped or encapsulated in microspheres or microparticles which can be administered into the surgical cavity by injection or infusion in the form of implant. Various publications describe release properties of local anesthetics from glyceride media, as follows.
Larsen, 2008; Drug Develop Indust Pharm, 34:297-304) discloses results of measuring rates of release of bupivacaine from various oils. Larsen discloses applying an in vitro measurement under nonsink conditions (rotating dialysis cell) to model drug release following intra-articular injection to a joint cavity. Larsen discloses rates of release of bupivacaine from fractionated coconut oil (a mixture of C8 and C10 saturated fatty acids) 80% release of the bupivacaine from the oil in less than two hours. Larsen also discloses results of measuring release of bupivacaine from MYRITOL® 318 PH (a triglyceride having a mixture of C8 and C10 saturated fatty acids) that were comparable to coconut oil. Larsen discloses that castor oil is considered the preferred excipient to modify drug release from oil solutions based on its history of parenteral administration. Larsen also discloses release rates of naproxen from a variety of oils, including MYRITOL® 318 PH, castor oil, SOFTIGEN® 701 alone or in combination with isopropyl myristate (IPM), and IMWITOR® 742 in combination with IPM, and that drug release rates from castor oil were slower than from other vegetable oils, most likely reflecting the hydrogen bond donating capability of the ricinoleic acid hydroxy group.
Castor oil has been used as a solvent in a commercial drug product AVEED® (testosterone undecanoate) injection for testosterone replacement therapy for intramuscular (gluteal muscle) administration. O'Hanlon, 2013, Lancet, special issue 1(S14) https://doi.org/10.1016/S2213-8587(13)70040-8. The U.S. Food and Drug Administration (FDA) found care must be taken to avoid intravascular injection because inadvertent escape of AVEED® into the vascular system may lead to vascular occlusion and short-term (60 minutes or less) consequences of pulmonary oil microembolism (POME) characterized primarily by cough, but sometimes with other associated symptoms. Id. The mechanical occlusion of the pulmonary vasculature from oil microembolization can cause acute transient pulmonary hypertension, resulting in a wide range of symptoms, from mild cough to circulatory collapse. It is postulated that POME results from microembolization of the oil drops to the lung vasculature, causing respiratory symptoms. Although other drug products also contain castor oil, the volume of castor oil in AVEED® is relatively greater than that of other products. Immediate/rapid release/dump of high volume of castor oil by IM injection may lead to vascular occlusion and potential short-term/transient POME.
Sundberg WO 2011/121082 discloses an aqueous stabilized pharmaceutical gelling composition comprising (a) an anesthetically effective amount of one or more local anesthetics selected from bupivacaine or lidocaine; (b) a monoglyceride or diglyceride, or mixture thereof of a long chain fatty acid in an amount of between 15 to 70% by weight, and (c) a free long chain saturated or unsaturated fatty acid, and/or (d) one or more solubilizers consisting of polysorbates, sorbitan fatty acid ester, glycerol formal, or a polyoxyethylated castor oil, in an amount of between 0 to 30% by weight. These compositions are for topical administration supported by results of an in vitro mucoadhesion test.
Richlin U.S. Pat. No. 7,666,914 discloses a composition for locally delivering and localizing comprising a local anesthetic agent selected from bupivacaine or mepivacaine, and an anti-inflammatory agent selected from ketoprofen, meloxicam, and naproxen.
While the above systems are useful, their manufacture processes are complicated, cumbersome and expensive. In addition, they are often associated with an initial higher release of drug immediately after injection (also called “burst”) followed by inconsistent and poor drug release kinetics, thus lack of reliability in pain relief in animal studies and human trials. There remains a need for controlled release of drugs suitable for pain management. Therefore, a more effective sustained release anesthetic is needed to effectively manage postsurgical pain with a rapid onset of action for coverage over the first crucial 24 hours and then prolonged duration through 72 hours.